Selective Estrogen Receptor Modulators Decrease the Production of Interleukin-6 and Interferon-γ-Inducible Protein-10 by Astrocytes Exposed to Inflammatory Challenge In Vitro
Selective Estrogen Receptor Modulators Decrease the Production of Interleukin-6 and Interferon-γ-Inducible Protein-10 by Astrocytes Exposed to Inflammatory Challenge In Vitro
复制标题
DOI：
10.1002/glia.20904
复制
发表时间：
2010-01-01
期刊：
影响因子：
6.2
通讯作者：
Arevalo, M. -A.
中科院分区：
文献类型：
--
作者：
Cerciat, M.;Unkila, M.;Arevalo, M. -A.
神经胶质细胞表达促炎分子参与与慢性神经系统疾病相关的病理生理变化。在病理条件下，星形胶质细胞释放许多促炎分子，例如白介素 6 (IL-6) 和干扰素 γ 诱导蛋白 10 (IP-10)。卵巢激素雌二醇对中枢神经系统发挥保护作用，这种作用至少部分是通过减少局部炎症来介导的。本研究旨在评估雌二醇是否会影响暴露于脂多糖（LPS）（一种已知会引起神经炎症的细菌内毒素）的新生小鼠星形胶质细胞的原代培养物产生的 IL-6 和 IP-10。此外，还评估了几种选择性雌激素受体调节剂（SERM）可能的抗炎作用。 LPS 诱导星形胶质细胞中 IL-6 和 IP-10 mRNA 表达水平的增加以及培养基中 IL-6 和 IP-10 蛋白水平的增加。 LPS 的这些作用受到雌二醇和我们研究中测试的四种 SERM 的损害：他莫昔芬、雷洛昔芬、欧司哌米芬和巴多昔芬。所有测试的 SERM 对 IL-6 和 IP-10 mRNA 水平均表现出类似的作用，但雷洛昔芬和欧司哌米芬在降低 LPS 处理的培养物中的蛋白质水平方面比他莫昔芬和巴多昔芬更有效。最后，我们报道了新的 SERM、欧司哌米芬和巴多昔芬通过涉及经典雌激素受体的机制和抑制 LPS 诱导的 NF kappa B p65 反式激活来发挥抗炎作用。结果表明，雌激素化合物可能是通过靶向星形胶质细胞产生和释放促炎分子来抵抗神经退行性疾病下脑部炎症的候选化合物。 (c) 2009 Wiley-Liss, Inc.
Expression of proinflammatory molecules by glial cells is involved in the pathophysiological changes associated with chronic neurological diseases. Under pathological conditions, astrocytes release a number of proinflammatory molecules, such as interleukin-6 (IL-6) and interferon-gamma-inducible protein-10 (IP-10). The ovarian hormone estradiol exerts protective effects in the central nervous system that, at least in part, may be mediated by a reduction of local inflammation. This study was designed to assess whether estradiol affects the production of IL-6 and IP-10 by primary cultures of newborn mice astrocytes exposed to lipopolysaccharide (LPS), a bacterial endotoxin known to cause neuroinflammation. In addition, the possible anti-inflammatory effect of several selective estrogen receptor modulators (SERMs) was also assessed. LPS induced an increase in the expression of IL-6 and IP-10 mRNA levels in astrocytes and an increase in IL-6 and IP-10 protein levels in the culture medium. These effects of LPS were impaired by estradiol and by the four SERMs tested in our study: tamoxifen, raloxifene, ospemifene, and bazedoxifene. All SERMs tested showed a similar effect on IL-6 and IP-10 mRNA levels, but raloxifene and ospemifene were more effective than tamoxifien and bazedoxifene in reducing protein levels in LPS-treated cultures. Finally, we report that news SERMs, ospemifene and bazedoxifene, exert anti-inflammatory actions by a mechanism involving classical estrogen receptors and by the inhibition of LPS-induced NF kappa B p65 transactivation. The results suggest that estrogenic compounds may be candidates to counteract brain inflammation under neurodegenerative conditions by targeting the production and release of proinflammatory molecules by astrocytes. (c) 2009 Wiley-Liss, Inc.